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Updated: Jun 20, 2025
Stimulation of Notch Signaling in Mouse Osteoclast Precursors
Published on: February 28, 2017
Signaling pathways associated with Lgr6 to regulate osteogenesis
Justin S King1, Matthew Wan1, Yadav Wagley2
1Department of Orthopaedic Surgery, The Musculoskeletal Research Institute, UCONN Health, Farmington, CT 06032, USA.
Abstract:
Fracture management largely relies on the bone's inherent healing capabilities and, when necessary, surgical intervention. Currently, there are limited osteoinductive therapies to promote healing, making targeting skeletal stem/progenitor cells (SSPCs) a promising avenue for therapeutic development. A limiting factor for this approach is our incomplete understanding of the molecular mechanisms governing SSPCs' behavior. We have recently identified that the Leucine-rich repeat-containing G-protein coupled receptor 6 (Lgr6) is expressed in sub-populations of SSPCs, and is required for maintaining bone volume during adulthood and for proper fracture healing. Lgr family members (Lgr4-6) are markers of stem cell niches and play a role in tissue regeneration primarily by binding R-Spondin (Rspo1-4). This interaction promotes canonical Wnt (cWnt) signaling by stabilizing Frizzled receptors. Interestingly, our findings here indicate that Lgr6 may also influence cWnt-independent pathways. Remarkably, Lgr6 expression was enhanced during Bmp-mediated osteogenesis of both human and murine cells. Using biochemical approaches, RNA sequencing, and bioinformatic analysis of published single-cell data, we found that elements of BMP signaling, including its target gene, pSMAD, and gene ontology pathways, are downregulated in the absence of Lgr6. Our findings uncover a molecular interdependency between the Bmp pathway and Lgr6, offering new insights into osteogenesis and potential targets for enhancing fracture healing.
Insights
Leucine-rich repeat-containing G-protein coupled receptor 6 (Lgr6) is crucial for skeletal stem cell function and bone healing. This study reveals Lgr6
Area of Science:
- Biochemistry
- Cell Biology
- Regenerative Medicine
Background:
- Fracture healing relies on bone's natural repair mechanisms, with limited therapeutic options.
- Targeting skeletal stem/progenitor cells (SSPCs) offers a promising therapeutic strategy for bone repair.
- Understanding the molecular regulation of SSPCs is critical for developing new treatments.
Purpose of the Study:
- To investigate the role of Leucine-rich repeat-containing G-protein coupled receptor 6 (Lgr6) in skeletal stem/progenitor cells (SSPCs) and osteogenesis.
- To explore the molecular mechanisms by which Lgr6 influences bone healing and osteogenic differentiation.
- To identify potential therapeutic targets for enhancing fracture healing.
Main Methods:
- Utilized biochemical approaches and RNA sequencing to analyze gene expression.
- Employed bioinformatic analysis of published single-cell data.
- Investigated Lgr6 expression during bone morphogenetic protein (Bmp)-mediated osteogenesis in human and murine cells.
Main Results:
- Identified Lgr6 expression in SSPC subpopulations, essential for bone volume maintenance and fracture healing.
- Demonstrated that Lgr6 influences both canonical Wnt (cWnt)-independent and -dependent pathways.
- Found that Bmp signaling elements, including pSMAD and gene ontology pathways, are downregulated in Lgr6-deficient cells.
- Observed enhanced Lgr6 expression during Bmp-mediated osteogenesis.
Conclusions:
- Uncovered a molecular interdependency between Bmp signaling and Lgr6 in osteogenesis.
- Lgr6 plays a significant role in regulating SSPC behavior and bone regeneration.
- These findings provide novel insights into osteogenesis and identify potential targets for improving fracture healing therapies.
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